Note from the National Guideline Clearinghouse (NGC) and the Institute for Clinical Systems Improvement (ICSI): For a description of what has changed since the previous version of this guidance, refer to Summary of Changes Report--October 2008.
The recommendations for the initial management of abnormal cervical cytology and human papilloma virus (HPV) testing are presented in the form of five algorithms with a total of 37 components, accompanied by detailed annotations. Algorithms are provided for: Initial Abnormal Cytology Result; Benign Endometrial Cells (BEC); Atypical Squamous Cells of Undetermined Significance (ASCUS); Atypical Glandular Cells (AGC); and Abnormal Cervical Cytology in Adolescents (Less than 21 years). Clinical highlights and selected annotations (numbered to correspond with the appropriate algorithm) follow.
Class of evidence (A-D, M, R, X) ratings are defined at the end of the "Major Recommendations" field.
Clinical Highlights
- Atypical squamous cells of undetermined significance (ASCUS) as an initial cytology result in women necessitates human papilloma virus (HPV) testing. If HPV testing is unavailable, a repeat Pap smear in six months or immediate colposcopy is recommended. (ASCUS Algorithm; Annotations # 7, 9; Aim #1)
- Atypical glandular cells (AGC) as an initial cytology result require a colposcopy and endocervical curettage (ECC) and possible endometrial biopsy. AGC cytology results can, in some cases, be indicative of extracervical malignancy. Follow-up is highly recommended. (AGC Algorithm; Annotation #18; Aim #1)
- Low-grade squamous intraepithelial lesion (LSIL) as an initial cytology result in an adult generally warrants a colposcopy. Special considerations may be made for adolescent and postmenopausal women. (LSIL Annotations #22, 23 and Abnormal Cervical Cytology in Adolescents Algorithm Annotation; Aim #1)
- High-grade squamous intraepithelial lesion (HSIL) as an initial cytology result requires colposcopy in adolescents or colposcopy with endocervical curettage (ECC) or loop electrosurgical excision (LEEP) in adults. (Annotations #24, 25; Aim #2)
- In adolescents, for ASCUS and LSIL cytologic screening results, the HPV regression rate is so high that conservative management without colposcopy is recommended. (Abnormal Cervical Cytology in Adolescent Algorithm, Annotations #30-34; Aim #1)
Introduction
The guideline group recognizes the difficulties faced by clinicians who must respond to abnormal cervical cancer screening test results. The group also recognizes this is an area of changing technology. Mindful of these concerns, the work group strives to present a framework based on objective evidence that will provide guidance to the clinician and patient in the management of abnormal cervical cancer screening test results.
Health Education
Receiving the diagnosis of an abnormal cervical cytology is a traumatic occurrence for many women. The work group was made aware of this fact repeatedly and felt that education attempts need to be improved if patient anxiety is to be successfully reduced. It was felt that written general information provided at the time of the initial cervical cancer screening test could serve to educate patients about the role of cervical cytology, as well as to provide basic information about some of the potential results, and to emphasize the fact that most such findings may require nothing further than repeating the cytology or undergoing relatively simple evaluations such as colposcopy. It was felt to be imperative that physicians or health care personnel who provide the initial diagnosis of an abnormal result to a patient have sufficient training to allay most fears and answer basic questions. Finally, it was felt that mailing written material specific to the diagnosis and recommended procedures and follow-up would help prepare the patient for the next phase of evaluation. With a commitment to such education and continued sensitivity to the anxiety produced by the finding of an abnormal cervical cytology result, physicians and other health care workers can provide effective and compassionate evaluation and treatment as needed.
Benign Endometrial Cells Algorithm Annotations
2-6. Benign Endometrial Cells (BEC) Present
Key Points:
- The Bethesda System 2001 reports the presence of normal, cytologically benign-appearing exfoliated endometrial glandular cells only in women age 40 or greater.
- Benign-appearing endometrial cells are noted in up to 12% of cervical cancer screenings performed over one year, more commonly in premenopausal than in postmenopausal women.
The presence of benign endometrial glandular cells on cervical screening tests may reflect physiologic shedding or shedding in response to a pathological process. In women over age 40, the presence of benign-appearing endometrial cells on cervical cytology has been found to be less than 2% [B]. Benign-appearing endometrial cells are more likely to be identified on cervical cytology in the first 10 to 12 days of the menstrual cycle (prevalence 21% to 24%) than in the remainder of the cycle (prevalence 2%) [B], [C]. The presence of benign endometrial cells on cervical cytology is reported so that a clinician can determine the significance of the finding in an individual woman.
Eighty-four percent (84%) of pre- and postmenopausal women who underwent endometrial sampling due to findings of benign endometrial cells on cervical pathology had no pathology, benign pathology or nondiagnostic pathology. Sixteen percent (16%) of these women were found to have significant pathology (simple or complex hyperplasia with or without atypia or carcinoma) at the time of their endometrial sampling [R].
If a woman has symptoms of endometrial cancer (abnormal uterine bleeding/spotting) or she is at increased risk of endometrial cancer (i.e., postmenopausal; family or personal history of ovarian, breast, colon or endometrial cancer; tamoxifen use; chronic anovulation; obesity [D]; or prior endometrial hyperplasia), a sampling of the endometrium with endometrial biopsy or dilation and curettage (D & C) is suggested to rule out endometrial cancer. If the above symptoms or risk factors are not present, routine gynecological care should be continued, as women have not been proven to be at increased risk of endometrial cancer based on the presence of benign endometrial cells on cytology alone [B], [C], [D].
Atypical Squamous Cells of Undetermined Significance (ASCUS) Algorithm Annotations
- Atypical Squamous Cells of Undetermined Significance (ASCUS) Present
Key Points:
- Atypical squamous cells of undetermined significance (ASCUS) is used by pathologists to denote cellular changes that are more marked than those attributable to reactive changes, but that are quantitatively or qualitatively short of a definitive diagnosis of squamous intraepithelial lesion (SIL).
The new Bethesda System has identified criteria for ASCUS on cervical cytology screening. Atypical squamous cells of undetermined significance (ASCUS) is used by pathologists to denote cellular changes that are more marked than those attributable to reactive changes, but that are quantitatively or qualitatively short of a definitive diagnosis of squamous intraepithelial lesion (SIL) [C], [D], [R].
Despite the evidence that supports a conservative approach, some clinicians favor immediate colposcopy for all ASCUS smears. The presence of these high-risk factors may influence the decision toward a more aggressive approach: teenage sexual activity, multiple sexual partners, intercourse with a male who has HPV, history of sexually transmitted disease or genital warts, tobacco use or history of tobacco use, intrauterine exposure to diethylstilbestrol (DES), poor compliance for follow-up, lack of normal immune response, no history of regular Pap smears, and age less than 30.
Advantages of immediate colposcopy for all ASCUS Pap smear results include:
- Reduced risk of missing a significant lesion
- Reduced risk of being lost to follow-up
- Faster reassurance to patient of normalcy or avoidance of multiple follow-up Pap smears, resulting poor compliance, and potentially overburdened clinics
- Avoidance of delay in diagnosis of cancer or high-grade cervical intraepithelial neoplasia (CIN)
Options for evaluation include triage to colposcopy by HPV deoxyribonucleic acid (DNA) testing, immediate colposcopy, or repeat cytology tests at 6 and 12 months [R].
- Repeat Cytology at 6 and 12 Months or Do Colposcopy
Key Points:
- Two consecutive negative cytology results at 6 and 12 months approach the sensitivity of a single HPV test for the detection of CIN-2/3 or greater.
- Immediate colposcopy may be an option for some women who have an initial cytology result of ASCUS.
One option for the low-risk reliable patient with an ASCUS result would be to have a follow-up cytology test at 6 and 12 months. Two consecutive negative follow-up tests will approach the sensitivity of a single HPV test for the detection of CIN-2/3+. Routine testing can be resumed after normal results at 12 months. If either is ASCUS or higher, colposcopy is recommended [R].
- ASCUS with High-Risk HPV DNA Positive?
Key Points:
- It is now scientifically well established that human papillomavirus (and more specifically, certain DNA subtypes like #16 and #18) has an important role in the progress of cervical dysplasia and development of squamous cervical cancer in almost all cases.
- Some experts advocate follow-up HPV DNA testing for ASCUS Pap smears. It is the consensus of the work group that this is an excellent option.
The work group is advocating the use of HPV testing to help triage patients with ASCUS. It can be cost-effective when done in a setting that includes liquid-based cytology collection methods, since the residual fluid can be saved for HPV analysis rather than calling the patient back for sampling. Since HPV testing is another viable option for evaluation of the ASCUS cytology result, colposcopy could be deferred and performed only for those women who have tested positive for high-risk HPV types [D], [R].
Clinicians ordering HPV tests should be aware of the strengths and limitations of the assay. The report that clinicians will receive from the high risk assay will often state that the patient tested positive or negative for "one or more of the following high-risk types" followed by a list of the HPV types. The careful wording is intended to convey to clinicians that the assay does not test for all HPV types known to associate with cervical cancer. A positive test for high-risk HPV types should indicate a need to educate the patient about HPV infection. A colposcopic examination should be scheduled. A negative HPV test result tells the clinician that the patient does not have a detectable burden of the high-risk virus types included in the test. The patient may, however, have a high-risk type at a lower titer than that which is reliably tested for or the patient may have an infection with a high-risk HPV type that is not part of the HPV assay.
- Repeat Cytology at 12 Months
Women who test negative for high-risk HPV can be reassured that their risk of having CIN-2/3+ is less than 2%. They can be scheduled for repeat cytology in 12 months.
- Colposcopy
Women who test positive for high-risk HPV have a 15% to 27% chance of having CIN-2/3 or worse. They should be scheduled for colposcopy. The exception to this recommendation is the adolescent, for whom the risk of invasive cancer approaches zero and the likelihood of HPV clearance is very high [C].
14, 15. Atypical Squamous Cells: Cannot Exclude High-Grade Squamous Intraepithelial Lesion (ASC-H) Present
The Bethesda System 2001 recognizes a new category of atypical squamous cells -- high grade dysplasia (ASC-H) cannot be ruled out. In the 1988 system, emphasis was placed on identifying all squamous intraepithelial lesion (SIL) Paps, including LSIL and HSIL. Currently, the emphasis of the Bethesda System 2001 is to identify HSIL and cytology associated with histologically proven high-grade disease.
ASC-H is thought to include 5% to 10% of all ASC cases and includes mixtures of true HSIL and mimics. The positive predictive value of ASC-H in detecting CIN-2 and CIN-3 lies somewhere between 48% and 56% [D], [R].
Colposcopic examination is the established appropriate evaluation of women with ASC-H Pap smear reports, regardless of the patient's HPV status. ECC should be performed if no lesion can be visualized. Initial evaluation of the ASC-H Pap smear should not routinely include the use of loop electrosurgical excision (LEEP).
Atypical Glandular Cells (AGC) Algorithm Annotations
16, 17. Atypical Glandular Cells (AGC) Present
AGC is a rare finding; it is present in less than 0.5% of cervical-cancer screening specimens. The causes of AGC include cervical and uterine adenocarcinoma, inflammation, hyperplasia, dysplasia, and (rarely) metastatic cancer. Therefore aggressive further evaluation is important [C].
Atypical glandular cells (which can be either uterine or cervical in origin) have enlarged nuclei, decreased cytoplasmic volume, and a variety of other unusual characteristics. Cells are classified as AGC (atypical glandular cells) with one of the following subheadings: NOS (not otherwise specified), FN (favor neoplasia) and favor either endocervical or endometrial origin.
- Perform Colposcopy/Endocervical Curettage/Endometrial Biopsy/HPV DNA Testing
Atypical glandular cells may indicate precancerous change or frank malignancy. Colposcopic evaluation including endocervical curettage should be used to evaluate for CIN and adenocarcinoma of the cervix. HPV DNA testing should be done to stratify the risk of cervical dysplasia and neoplasia. Endometrial tissue sampling should be used to assess for endometrial cancer and hyperplasia. A pathologist should correlate the histology of the endometrial tissue with the cells on the original cytology screening specimen so as to explain the original abnormality. If the sampling does not explain the original abnormality, the provider should refer the patient to a gynecologist or a gynecologic oncologist. Findings from these initial steps will dictate further evaluation and treatment.
- Low-Grade Squamous Intraepithelial Lesion (LSIL) Present
The LSIL category includes changes consistent with human papillomavirus (HPV), mild dysplasia or CIN-1 (grade 1 cervical intraepithelial neoplasia). Eighty percent (80%) will be high-risk HPV positive and 15% to 30% have moderate or severe dysplasia at initial colposcopy. The ALTS group could not identify a useful triage strategy for this category that could spare colposcopic evaluation. Therefore colposcopy is recommended for initial evaluation of LSIL [B], [R].
There is consensus and expert opinion that follow-up without immediate colposcopy may be appropriate in the postmenopausal patient. HPV prevalence is low, allowing for triage with HPV testing. If negative, patients can return to routine surveillance [R].
- Colposcopy
The most common management option is to perform a colposcopy. One must be cautious about over-aggressive biopsy and treatment. Specifically, routine LEEP of the transformation zone as a method for evaluating a LSIL Pap smear is not recommended.
Rate of regression has been quoted as high as 62% to 80% on follow-up. (Some investigators believe this reported regression rate is falsely high because prior biopsy, in effect, "treated" the original lesion. Under this assumption, regression rates of unbiopsied low grade lesions may be as low as 25%) [C], [R].
- High-Grade Squamous Intraepithelial Lesion (HSIL) Present
The Bethesda System 2001combines moderate dysplasia with severe dysplasia and carcinoma-in-situ (CIS) into a single category of high-grade intraepithelial lesion (HSIL). Up to 95% of patients with high-grade cervical cytology results have been found to have high-grade lesions [C].
Of all the categories in current nomenclature for cervical cytology results, perhaps the least ambiguity and the least controversy in management is with HSIL. Histologic evaluation of directed cervical biopsies from women with HSIL will commonly show moderate or severe dysplasia or even carcinoma in situ. Thus the standard of practice for management is clearly to perform colposcopy and directed biopsy [C].
Further management of the patient will then be guided by the biopsy results [R].
- Colposcopy with Endocervical Curettage (ECC) or Loop Electrosurgical Excision (LEEP)
Colposcopic examination with ECC-directed biopsies or LEEP is the appropriate management for women with HSIL cytology results. If follow-up for the patient is unreliable or in a "see and treat" circumstance, LEEP may be performed immediately. When a LEEP is performed immediately it is not necessary to automatically do an ECC. But if endocervical disease is suspected as a result of the colposcopy and LEEP is not done, an ECC should still be performed [M], [R].
- HPV DNA Testing Positive with Normal Cytology
In 2003, the Food and Drug Administration approved HPV DNA testing in conjunction with cervical cytology screening for women aged 30 years and older [R]. Due to the high prevalence and spontaneous clearance of HPV DNA in adolescents and women in their 20s, HPV DNA should not be used for routine screening before age 30 [R].
The use of HPV DNA testing as an adjunct to cervical cytology for women aged 30 years and older increases the sensitivity of cervical cancer screening. Review of recent screening studies reported pooled sensitivity and specificity of HPV DNA testing for CIN-2/3+ for women 35 years and older was 95% and 93%, respectively [C]. Sensitivity using a combination of HPV DNA testing and cervical cytology was higher than either test alone; negative predictive values were 99% to 100% [R].
Based on this kind of evidence, the American Cancer Society and subsequently the American College of Obstetricians and Gynecologists both concluded this combination of HPV DNA testing and cervical cytology was a reasonable screening strategy for women aged 30 years and older [B], [R]. Furthermore, testing should not be done more often than every three years if both results are negative, based on a study showing less than 2% of patients with negative HPV DNA and cervical cytology screening developed CIN-3+ in 10 years of follow-up [B]. As there is no evidence of improved outcomes with this combination of screening tests, screening with cervical cytology alone remains an acceptable screening option.
Many women screened with a combination of HPV DNA and cervical cytology will test positive for HPV DNA and simultaneously have a negative cervical cytology. The risk for undetected CIN-2/3+ for patients with such a combination of screening results is quite low, with published study results varying from 2.4% to 5.1% [A]. Based on this low risk for CIN-2/3+, repeat HPV DNA testing combined with cervical cytology in 12 months appears to be reasonable for patients in this group. If the HPV DNA test remains positive on the repeat screening, the patient should undergo colposcopic evaluation despite a second negative cervical cytologic result [R].
Abnormal Cervical Cytology in Adolescents (Less than 21 Years) Algorithm Annotations
30-37. Abnormal Cytology Results in Adolescents Present
Key Point:
- In adolescents, the HPV regression rate is so high that conservative management without colposcopy is recommended.
Management of ASCUS Cervical Cancer Screening Test Results in Adolescents
A report of ASCUS on a cervical cytological screening test often indicates a woman is harboring an HPV infection. In the adolescent population, the prevalence of HPV in that subset with an ASCUS report will be much higher than in an older population. As noted, the risk of invasive cancer in adolescents approaches zero, and the likelihood of HPV clearance is very high.
The preferred method of triage for adolescent patients with ASCUS is monitoring with cytology at 12 months intervals. If the repeat cytology test results are abnormal for 24 months, colposcopy should be performed. These alternatives avoid the expense of colposcopy and biopsy, and they allow for the high likelihood of clearance of CIN-1 and HPV in this population [B], [R].
Immediate colposcopy is an acceptable alternative for the management of the adolescent who tests positive for ASCUS and LSIL if follow-up is problematic.
Management of LSIL Cervical Cancer Screening Test Results in Adolescents
The ALTS trial showed that patients with cytological report of LSIL and ASCUS behave in a similar manner regarding clearance of HPV and the risk of developing CIN-2/3+. Due to the similarities in the natural history of these cervical cancer screening findings, management for adolescents is the same as for ASCUS [R].
Management of All Cervical Cancer Screening Test Results with High Probability of CIN-2/3+ in Adolescents
Screening test results of ASC-H, HSIL and AGC all indicate a higher probability for a CIN-2/3+ lesion and should be managed by immediate colposcopy and endocervical assessment as for older women. The management algorithm is identical to the main algorithm for these cervical cancer screening test results [R]. However, immediate loop electrosurgical excision (LEEP) is not recommended in adolescents since surgical excision may be detrimental to future fertility and cervical competency.
Surgical treatment should be delayed until persistent disease is proven.
In pregnancy, the only diagnosis that may alter clinical management is invasive cancer. The presence of cancer may change treatment goals for the route and timing of delivery. Cervical cancer screening test results that are not likely to be associated with cancer may undergo colposcopic evaluation either during pregnancy or 8 to 12 weeks postpartum. Pregnant women whose screening test results indicate a high risk for CIN-2/3+ should undergo colposcopy without endocervical sampling, reserving biopsy for visible cervical lesions consistent with CIN-3, AIS or cancer [R].
Definitions:
Classes of Research Reports:
- Primary Reports of New Data Collection:
Class A:
- Randomized, controlled trial
Class B:
Class C:
- Non-randomized trial with concurrent or historical controls
- Case-control study
- Study of sensitivity and specificity of a diagnostic test
- Population-based descriptive study
Class D:
- Cross-sectional study
- Case series
- Case report
- Reports that Synthesize or Reflect upon Collections of Primary Reports:
Class M:
- Meta-analysis
- Systematic review
- Decision analysis
- Cost-effectiveness analysis
Class R:
- Consensus statement
- Consensus report
- Narrative review
Class X:
